Hereditary hyperparathyroidism: Familial Hypercalcemia Hypercalciuria Syndrome

Familial Hypercalcemia Hypercalciuria Syndrome or Autosomal Dominant Moderate Hyperparathyroidism (ADMH)

Carling et al. reported a large family with 20 members, from different generations, affected by this syndrome (OMIM 601199) (Table I). These subjects did exhibit hypercalcemia and hy- percalciuria, with an inappropriately high serum PTH and magnesium levels and with nephrolithiasis in a subset of patients.

Pathology

Uni-, multi-glandular involvement of parathyroid glands was found and diffuse to nodular parathyroid neoplasia has been reported on pathological examination (Table III).

Molecular aspects

DNA test revealed the presence of an atypical inactivating mutation in the intra-cytoplasmic tail domain of CaSR in the germline of affected subjects (Table II). LOH analysis revealed allelic losses at various genetic loci, consistent with mono- or oligoclonality of parathyroid tumors.

Hereditary hyperparathyroidism: Familial Hypercalcemia Hypocalciuria Syndrome

Familial Hypercalcemia Hypocalciuria Syndrome (FHH)/ Neonatal Severe Hyperparathyroidism (NSHPT)

FHH (OMIM 145980) (Table I) is a rare disorder inherited in au- tosomal dominant manner and characterized in the adult by the outcome of increased/normal levels of serum calcium, moderate hypophosphoremia, increased/normal circulating PTH levels, that are frequently inadequate when correlated to serum calcium levels and an inappropriately low urinary calcium excretion. The majority of patients with FHH are asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroid that cannot correct the calcium-dependent PTH secretion set-point abnormality. FHH-related hypercalcemia is highly penetrant at all ages. Generally, these patients show relative hypocalciuria (urinary calcium/creatinine ratio typically <001) in the presence of hypercalcemia and hyperparathyroidism due to inactivation of CaSR protein in renal tubules. Moreover, a mild hypermagnesemia can be found. NSHPT (OMIM 239200) (Table I) generally represents the ho- mozygous form of FHH, in which PHPT occurs at birth or within the first 6 months of life determining a severe symptomatic hy- percalcemia, with skeletal manifestations of PHPT and if neck surgery is not promptly performed a lethal outcome may occur.  

Pathology

PHPT in the setting of FHH is generally sustained by the presence of mildly enlarged parathyroid glands, whereas markedly hyperplastic parathyroid glands are a typical feature of NSHPT-related PHPT (Table III).

Molecular aspects

Inactivating mutations, with a loss of function, of CaSR gene, localized at chromosome 3q13-21, account for both the forms (92, 93) (Table II). CaSR protein is a membrane protein consisting of 1078 amino acids, mainly expressed by kidney and parathyroid cells, belongs to the G proteins-coupled receptor (GPCR) superfamily. The CaSR is able to sense small changes in circulating calcium concentration and when activated it inhibits PTH secretion and renal tubule calcium reabsorption. The described mutations in FHH and NSHPT subjects are prevalently localized in the calcium binding site of extracellular portion of receptor. Inactivation of this GPCR protein results in half-maximal inhibition of PTH secretion only at increased concentrations of serum calcium (calcium set-point), although the magnitude of PTH suppression by increased serum calcium concentrations is normal in patients with FHH. Somatic mutations within the CaSR gene, which would explain impaired function and altered receptor expression, have not been detected both in sporadic and familial forms of parathyroid tumors thus far.

Treatment of FHH/NSHPT-PHPT manifestations

Although it is generally accepted that FHH patients do not benefit from surgery of parathyroid lesions, subtotal parathyroidectomy can be performed in subjects developing symptomatic PHPT (Table III) who may have an underlying polyclonal parathyroid cell hyperproliferation due to a heterozygous inacti- vation of CaSR or to another hypothetical acquired genetic defect in a different gene. When performed the neck surgery in FHH subjects may include subtotal parathyroidectomy leaving 10-20 mg of parathyroid tissue in order to achieve normocalcemia (Table III). In all cases, cryopreservation of parathyroid tissue should be considered. Total parathy- roidectomy must be performed in the first months of life in NSHPT affected infants (Table III).
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Hereditary hyperparathyroidism: Hyperparathyroidism-Jaw Tumors (HPT-JT) syndrome

HPT-JT (OMIM 607393) is a rare autosomal dominantly inherited disorder characterized by fibrous-osseous tumors of mandible and/or maxilla (ossifying fibroma), Wilms' tumor, papillary renal carcinoma, polycystic kidney disease, renal cysts and PHPT. The latter exhibits an aggressive behavior within this syndrome and it is frequently sustained by parathyroid carcinoma.

In the context of PHPT-related syndromes (Table I), HPT-JT syndrome is one of the least common and relatively unknown pictures, although not less interesting or important. About 80% of patients present with PHPT, that may develop in late adolescence or older. A reduced penetrance in females has been reported, and parathyroid carcinoma may occur in approximately 10-15% of affected individuals. When compared to MEN1-related PHPT, HTP-JT syndrome may run a more aggressive course: the patients tend to have more severe hypercalcemia and hypercalcemic crisis could represent the first clinical evidence. In order to monitor the presence/absence of PHPT, HPT-JT patients should undergo annual blood tests evaluating ionized calcium and intact parathyroid hormone (iPTH) levels, beginning by 15 years of age. However, it should be taken always into account, due to their possible severity, that lesions in the maxilla, mandible, kidney, and uterus should be carefully monitorized by imaging studies (i.e. orthopantography of the face, perhaps once in every 3 years, and annual abdominal ultrasound or computed tomography scan).

Pathology

PHPT in HPT-JT syndrome generally consists of involvement of one or two parathyroid glands (adenoma or double adenoma) (Table III) that may be or may be not synchronously present, differently from the MEN1-PHPT in which all glands are frequently involved. Parathyroid carcinoma may occur in approximately 10-15% of affected individuals. The high incidence of cystic figure in resected parathyroid glands represents a classical pathological feature of parathyroid neoplasia in HPT-JT syndrome. In fact, due to frequent identification of parathyroid recurring cystic adenomas this clinical entity can be referred to also as familial cystic parathyroid adenomatosis (Table III). The jaw lesions typically associated to this syndrome have been reported to be histologically distinct from the typical ones representing the bone disease classically associated to PHPT.

Molecular aspects

Very recently, the HRPT2 gene, responsible for this syndrome, has been identified in the "tumor suppressor gene" parafi- bromin, previously mapped at 1q25-q32 (Table II). This gene appears to be involved also in the pathogenesis of sporadic forms of PHPT. Fourteen germline inactivating mutations of HPRT2 gene were identified in 26 kindreds (Table II). The gene encodes a protein of 531 amino acids, named parafi- bromin, involved in the development of parathyroid tumors and ossifying fibromas. To date, the protein does not exhibit any homology to known protein domains. The gene appears to be ubiquitously expressed in several human tissues such as kidney, heart, liver, pancreas, skeletal muscles, brain and lung. However, its role in development and tumorigenesis still remains to be elucidated.

Loss of wild-type alleles in HPT-JT syndrome was found both in renal and parathyroid tumors. These findings, together with the inactivating nature of the germline mutations strongly suggest a tumor suppressive role for parafibromin. Such LOH are not as frequent as reported in MEN1-related tumors. To date, it has been no possible to describe a genotype-phe- notype correlation and more data from other affected families and from genetic studies are necessary to possibly determine the eventual existence of such a correlation. However, the possibility to perform DNA test provides the great opportunity for an early identification of an asymptomatic gene carrier who will receive the needed stringent clinical screening procedures.

Treatment of HPT-JT-PHPT manifestations

As soon clinical evidence of PHPT as occurred, neck surgery should be promptly performed. However, a general consensus on which type of surgical approach should be adopted, if removal of the enlarged gland with long-term follow-up or complete parathyroidectomy followed by auto-transplantation to the nondominant forearm has not been reached. For parathyroid carcinoma neck surgery, specifically an en bloc resection of primary tumor, is the only curative treatment (Table III). Alternatively, affected patients could undergo repetitive palliative surgical exeresis of metastatic nodules.
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Hereditary hyperparathyroidism: Familial Isolated PHPT (FIHPT)

FIHPT (OMIM 145000) is a rare hereditary disorder characterized by uni- or multiglandular parathyroid lesions in the absence of hyperfunction in other endocrine tissues (Table I). FIHPT is transmitted in an autosomal dominant manner. Few large families have been shown to be linked to MEN1 gene, or to calcium sensing receptor (CaSR) gene mutations, while other families exhibit a segregation of phe- notype with DNA markers close by the Hyperparathyroidism- Jaw tumors (HPT-JT) syndrome locus at 1q25-q32. Most of FIHPT kindreds have currently an unknown genetic background (Table II). To date, approximately over 100 FIHPT families have been described.

In deed, the clinical management of this form could be complex, although the generic surgical principles of PHPT treatment can be generally applied.
Pathology

Unior multiglandular involvement represents the most frequent pathological picture underlying the parathyroid hyper- function (Table III). Progression to malignancy have not been reported for affected subjects with solitary parathyroid adenoma from two FIHPT families mapped to the same region as the HPT-JT syndrome on chromosome 1q21-q32.

Molecular aspects

No gene has yet been associated exclusively with FIHPT. However, as mentioned above, FIHPT has been linked to mutations in the MEN1, and CaSR genes, whereas in some families genetic linkage to these loci was not established. All this is consistent with a genetic and clinical heterogeneity of this form of PHPT. Carpten et al. reported in a patient from one of the two FIHPT families mapped to chromosome 1q21-q-32, a mutation in HRPT2 gene, confirming the they are allelic to the HPT-JT syndrome (Table III).

Treatment of FIHPT manifestations

In a case of uniglandular disease, parathyroid adenomectomy can be performed, whereas for multiglandular involvement a subtotal parathyroidectomy or total parathyroidectomy, with autologous reimplantation, can be considered (Table III). Of course, FIHPT linked to mutations in MEN1 or HRPT2 genes should be treated similarly to MEN1- and HPT-JT-associated PHPT, respectively, since the patient may be from a kindred with absent or low penetrance of other associated tumor types.
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Hereditary hyperparathyroidism: Multiple Endocrine Neoplasia

Multiple Endocrine Neoplasia type 2A syndrome (MEN 2A)

MEN2A is a clinical variant of MEN2 syndrome (OMIM 171400) and it specifically carries an increased risk for parathyroid adenoma or hyperplasia (Table I). Similarly to MEN1 also this syndrome is inherited in an autosomal dominant manner with a high degree of penetrance and clinical variability. MEN2A variant is clinically characterized by the occurrence of medullary thyroid carcinoma (MTC), nearly in the 100% of affected subjects, pheochromocytoma, bilateral or unilateral, in 50% of patients, whereas the PHPT is described in 20-30% of MEN2A cases.

MEN2A-associated PHPT

PHPT in MEN2A is less common than in MEN1 syndrome, occurring in 20 to 30% of the patients.

MEN2A-associated PHPT may silently occur for several decades. It is sustained by the presence by multiple adenomas or, less frequently, parathyroid hyperplasia and it exhibits a less aggressive behavior respect to the MEN1-associated PHPT, usually occurring after the third decade (Table II). Generally, MEN 2A-related HPT is also mild and asymptomatic, with approximately 15-25% of the patients developing clinical signs of their disease.

Hereditary hyperparathyroidism: Molecular aspects

Germline inactivating mutations of MEN1 gene have been found in most of the affected from MEN1 kindreds (Table II). Recent advances on pathophysiological roles of menin, the protein product of MEN1 gene, disclose the existence of an intricate network composed by several molecular partners interacting with menin: Smad3, TGFP, JUND, GFAP, vimentin, NF- kB, NM23H1, ERK, JUNK, Elk-1 and c-Fos. However, it is still completely unknown how mutations in menin cause tumorigenesis, nor is the function of menin. Menin may play different roles in different tissues interacting with such different proteins, but also the interacting proteins of such a molecular network may have a role in both the onset and progression of MEN1-associated tumors.
However, MEN1 parathyroid tumorigenesis has been widely demonstrated to progress through the inactivation of the "wild type" allele of MEN1 gene, a tumor suppressor gene, at somatic level indirectly evidenced as loss of heterozygosity (LOH) at 11q13 or intragenic DNA markers. After the cloning of MEN1 gene the early detection of asymptomatic carriers dra-matically decreases the morbidity and mortality of MEN1 syndrome, providing the opportunity to initiate appropriate treatment at early stages.

Hereditary hyperparathyroidism: Genetic aspects in familial forms of PHPT

Molecular genetics strongly contributed to clearly evidence that PHPT may also occur as a familial cluster (Table I). In Table II familial hyperparathyroid disorders with their main genetic features are briefly summarized. In any case, each of the following described syndromes should be clinically approached through a differential diagnosis. In deed, a differential diagnosis will include an integrating approach to all the hereditary forms of PH- PT.

MEN1

MEN1 (OMIM 131100) is a complex tumor-predisposing disorder inherited in an autosomal dominant manner with a high degree of penetrance, nearly 100% within 50 years of age. The syndrome exhibits a high grade of clinical variability, also in members from the same affected family. More than 20 combinations of both endocrine and nonendocrine tumors have been reported in MEN1 patients, with three endocrine localizations constituting the "typical" clinical features of this syndrome: multiple tumors of parathyroid glands (generally all the parathyroid glands), pituitary adenomas and tumors of the neuroendocrine cells in the gastroenteric tract. Advances in molecular biology and genetics have led to the identification of the specific genetic defect, at chromosome 11q13 (Table II), improving the understanding and ability to early diagnosis this syndrome.

MEN1-associated PHPT

MEN1-PHPT represents the most common endocrinopathy associated to MEN1 syndrome, accounting for the 2-4% of global PHPT forms and it represents the first clinical expression of MEN1 syndrome in approximately 90% of individuals. It does not exhibit sex prevalence and its age onset is typically between 20 and 25 years (Table II), three decades earlier than the sporadic cases of PHPT. Its penetrance reaches 100% with age and all MEN1 affected individuals are expected to have hypercalcemia by age 50 years.

MEN1-PHPT is often mild and asymptomatic with biochemical evidence of hypercalcemia often detected in the course of evaluation of individuals known to have or be at risk for MEN1 syndrome. However, even if the MEN1-associated PHPT is frequently asymptomatic for a long period of time, a reduced bone mass can be observed in hyperparathyroid women as early as 35 years of age.

Table II - Chromosomal localization and genetic defects underlying each familial form of hereditary hyperparathyroidism.

Syndrome/OMIM#°	Chromosomal localization	Gene/activity	Type of germline mutation
MEN1/131100	11q13	MEN1/oncosoppressor	Inactivating
MEN2A/171400	10q11.1	RET/proto-oncogene	Activating
FIHPT/145000	11q13*, 1q25-q31*, 3q13.3-q21*, and still unknown loci	MEN1/oncosoppressor, HRPT2/oncosoppressor, CaSR/GPCR and still unknown genes	Inactivating for MEN1, HRPT2, and CaSR genes
HPT-JT/607393	1q25-q31	HRPT2/oncosoppressor	Inactivating
FHH-NSHPT/145980-239200	3q13.3-q21	CaSR/GPCR	Inactivating
ADMH/601199	3q13.3-q21	CaSR/GPCR	Atypical inactivating

The common clinical manifestations of hypercalcemia are similar to those observed in nonhereditary sporadic form of PHPT. However, it must be taken into account that hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome, a clinical picture frequently associated to MEN1 syndrome.

Pathology

MEN1 affected subjects generally exhibit a multiglandular parathyroid disease with the enlargement of all the parathyroid glands, rather than a single adenoma (Table II); they are considered to be tumors of clonal origin. Asymmetric and asynchronic parathyroid outgrowth involves all parathyroid glands in these patients and after 8-10 years from sub-total parathyroidectomy a 50% of recurrence of PHPT has been observed. This could be due to an onset of a new tumor in the context of the parathyroid tissue remnant or, alternatively, to the growth of an unremoved tumor. Malignant progression of parathyroid tumors is not a clinical feature observed in "classic" MEN1 syndrome.
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